Mammalian target of rapamycin (mTOR) is an atypical serine/threonine protein kinase, is a member of the phosphoinositide 3-kinase (PI3K) related kinase family, and is a main signaling molecule of cell functions such as intracellular synthesis and catabolism. The mTOR signaling pathway has a close relationship with nutrition, energy states and growth factors, and modulates many cellular processes including autophagy, protein, lipids and lysosomes synthesis and energy metabolism, cytoskeleton organization, cell survival, and so on. Under the changing peripheral nutritional conditions of mammalian cells, mTOR regulates the conversion between synthesis and degradation metabolism to enable the cells to grow and survive under different nutritional conditions. Because of the important role of mTOR in cells, aberrant or deregulated mTOR signaling can lead to human diseases (such as cancer and other diseases). Therefore, the mTOR signaling pathway is becoming an important target for the design of anticancer drugs.
The activation of the PI3K/Akt/mTOR signaling pathway is closely related to a variety of tumorigenesis. mTOR can accelerate cell cycles, reduce apoptosis and promote tumor cell migration in brain glioma, breast cancer, and ovarian cancer. Activation of mTOR begins at several ligand-activated growth factor receptors on the cell surface, such as epidermal growth factor receptor and insulin-like growth factor-1 and -2 (IGF-1 and IGF-2). The activation of the receptors leads to the activation of the PI3K kinase, thereby resulting in the activation of the downstream effector Akt protein. Akt is a regulatory factor that can regulate cell survival in multiple levels. After phosphorylation, Aid inhibits the downstream TSC1/2 complex, and thus mTOR is activated by Rheb. Downstream the PI3K/Akt and PEN/Akt and Ras/Erk1/2 signaling pathways, the TSC1/2 complex plays a vital role in the regulation of mTOR activation.
Two different mTOR protein complexes, i.e., mTORC1 and mTORC2, have been found in cells. Both protein complexes contain a unique protein interacting with mTOR, and are regulated by different mechanisms, respectively. Great progress has been made in the research and development of mTOR inhibitor drugs. Rapamycin is the first discovered mTOR inhibitor and has shown good tumor-inhibiting effects in a variety of cancer models. Although rapamycin analogues with better pharmacological properties have been developed, clinically applicable rapamycin analogues are only confined to a few cancers. The important discovery that Aid is an important kinase in the survival of cancer cells and mTORC2 can directly phosphorylate Aid provides a new way of thinking in the anti-cancer research with mTORC2, and at the same time contributes to the research and development of the second-generation anti-cancer drugs which act on both mTORC1 and mTORC2 targets. Simultaneous inhibition of the activities of both mTOR complexes (mTORC1 and mTORC2) in cancer cells provides a wider and more effective anti-cancer effect.
Compound 1, which has the chemical name of 1-((1 s,4s)-4-hydroxycyclohexyl)-3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-2(3H)-one, is a dual inhibitor of protein kinases PI3K/mTOR, and has a structure represented by the following formula:

Compound 1 and pharmaceutically acceptable salts thereof have been disclosed in WO 2015074516 A1, which report that they exhibit a good drug activity in cells and animal models. Therefore, the development of crystal forms of Compound 1 that are more stable, more suitable for formulation, and have better absorption and metabolism is of great significance for their clinical application.